4.0 ACCOUNTABILITY

5.0 REFERENCE (S)

6.0 PROCEDURE

6.1 EXIT AND ENTRY PROCEDURE

6.1.1 All Operators and Supervisors enter department as per Defined Gowning procedure.

6.2 AMPOULE FILLING MEDIA

6.2.1 The media fill run shall be performed for approximately the same duration as required for filling of a normal production batch (approx. 12 hours).

6.2.2 Batch (Media) manufacturing shall be done in the initial hours of the 1st shifts, followed by other processing steps normally followed.

6.2.3 Nitrogen flushing shall not to be done during media filling.

6.2.4 The filling of media shall be done in the following sequence:-

6.2.4.1 The media (Soybean Casien Digest Madium) batch shall be manufactured in the manufacturing area. The bulk is then aseptically filtered into a sterile holding tank (under LAF) in the sterile area. The tank containing the filtered solution is then connected sterile silicon pipeline and filling done in ampule without employing the use of on-line cartridge filters/filter housing on the machine.

6.2.4.2 Fill volume of media as per the protocol. (The fill volume of media in units need not equal the fill volume of finished product units, the quantity filled shall be sufficient to wet all the inner surfaces of the unit & to enable an inspection to detect positives.)

6.2.4.3 Filling activity is performed in the filling room (especially the filling zone) under LAF.

6.2.4.5 Simulate the adverse condition testing of the system (details of adverse conditions given separately in step 6.4) after filling approximately 10,000 units.

6.2.4.6 Filling to be planned in a manner such that the operator covers the activities during the shift change over.

6.3 VIAL FILLING MEDIA:

6.3.1 The media fill run shall be performed for approximately the same duration as required for filling of a normal production batch (approx. 12 hours).

6.3.2 Batch (media) manufacturing shall be done in the initial hours of the 1st shifts, followed by other processing steps normally followed.

6.3.3 Nitrogen flushing shall not be done during media filling.

6.3.4 The filling of the media to be done in the following sequence-

6.3.4.1 The media (Soybean Casien Digest Madium) batch is manufactured in the manufacturing area. The bulk is then aseptically filtered into a sterile holding tank (under LAF) in the sterile area. The tank containing the filtered solution is then connected with is sterile silicon pipeline and filling done in vials without employing the use of on-line cartridge filters/filter housing on the machine and then dosing of sterile lactose in vials.

6.3.4.2 Transfer the sterile lactose through material airlock into the sterile area and transfer the sterile lactose aseptically into the previously sterilized hopper of the vial filling machine. Three runs will be validated with 250 mg sterile lactose and 5 ml media solution, 500 mg sterile lactose with 5 ml media solution and 1000 mg sterile lactose with 10 ml media solution to validate the weight range from 250 mg to 1000 mg.

6.3.4.3 Fill volume of media or weight of Powder as per the protocol. (The fill volume of media filled units need not equal the fill volume of finished product units, the quantity filled shall be sufficient to wet all the inner surfaces of the unit & to enable an inspection to detect positives.)

6.3.5 Filling activity is performed in the filling room (especially the filling zone) under LAF.

6.3.6 Simulate the adverse condition testing of the system (details of adverse conditions given separately in step 6.4) after filling approximately 10,000 units.

6.3.7 Filling to be planned in a manner such that the operator covers the activities during the shift change over.

6.4 ADVERSE CONDITIONS: (AMPULE/ VIAL)

6.4.1 Filling machine OFF: For 60 minutes (The filtered air supply in the filling zone not to be put off. Imitate maintenance activities that are likely to take place during routine filling process, after restarting approx. 1,000 units to be filled)

6.4.2 LAF Filtration OFF: For 5 minutes (filling to be done when LAF is OFF)

6.4.3 Air Handling Units power OFF: For 5 minutes (ALL the AHU’s of the sterile and the adjoining areas to be switched OFF, filling to be done when AHU’s are OFF).

6.4.4 Total Power OFF for 2 minutes:

(ALL the AHU’s of the sterile and the adjoining areas, filling m/c, LAF’s etc to be switched OFF, after restarting approx. 1,000 units to be filled)

6.4.5 Highest (250 ampule/vial min.) speed of machine:

approx. 1,000 units to be filled

6.4.6 Change in tubing’s: Approx. 1,000 units to be filled

6.4.7 Ampule/Vial Sterilizing tunnel OFF: For 5 minutes (total power supply of the tunnel is to be switched OFF, after restarting tunnel all the units from the cooling zone to be filled).

6.5 STORAGE OF FILLING UNITS (AMPULE/VIAL)

6.5.1 Collect all units in a tray or suitable container, Store in previously maintained temperature defined area or incubator.

6.5.2 First Store at temperature 20 -25 ° C for seven days.

6.5.3 After that Store at temperature 30 -35 ° C for seven days.

6.6 RESULT

1. After the incubation period of the media-filled containers, they are visually examined for microbial growth. Contaminated containers should be examined for evidence of container/closure damage which might compromise the integrity of the packaging system. Damaged containers should not be included as failures (positives) when evaluating results.

2. The number of containers used for media fills should be sufficient to enable a valid evaluation. For small batches, the number of containers for media fills should at least equal the size of the product batch. The target should be zero growth and the following should apply:

• When filling fewer than 5000 units, no contaminated units should be detected.

• When filling 5,000 to 10,000 units,

a) One (1) contaminated unit should result in an investigation, including consideration of a repeat media fill;

b) Two (2) contaminated units are considered cause for revalidation, following an investigation.

• When filling more than 10,000 units:

a) One (1) contaminated unit should result in an investigation;

b) Two (2) contaminated units are considered cause for revalidation, following an investigation.

Abstracted from:PIC 007-5 dated 01 July 2009Recommendation on the Validation of aseptic processes.

6.7 DESTRUCTION OF MEDIA:

6.7.1 After 14 days media shall be destructed as per sop or procedure.

6.8 FREQUENCY OF MEDIA FILLS (AMPULE/VIAL):

6.8.1 Initial Three consecutive Successful Run(all container size employed for filling on the machine) before start production for qualified area or equipment.

6.8.2 Then after once in 6+1 month of Single run any suitable volume for re-qualification of area or equipment.

6.8.3 If any change or modification of critical equipment or area then goes for single run media for any suitable volume before starting production.

6.8.4 If critical equipment or area is not in use for about one month then go for single run media for any suitable volume before starting production.